Protein biosynthesis is the end product of genetic expression in all living cells. The ribosome acts as a focal point for all protein synthetic precursors and thus represent an attractive target of exploitation for the development of antitumor, antiviral, antibiotic, and antitrypanosomal agents. The antibiotics, puromycin, chloramphenicol, and sparsomycin inhibit protein synthesis in a wide variety of microorganisms. The common feature of these antibiotics is their ability to bind to the ribosomal peptidyltransferase site. Chloramphenicol exhibits only antibacterial activity while puromycin and sparsomycin also bind to mammalian ribosomes and are antibacterial/antitumor agents. This species selectivity in ribosomal binding has provided the basis for useful therapeutic activity, but the potential exploitation of the ribosome for the development of synthetic agents has not been actively explored. This is perhaps due to the complexity of the ribosomal system and the requirement for a highly integrated program involving synthetic work with a strong biological component. Our program is designed to provide synthetic models to study the binding requirments of various molecules that interact with the ribosomal peptidyltransferase site (the site of peptide bond formation). Our main projective is to prepare inhibitors of protein synthesis and to study the mechanism of peptide bond formation. Previous modifications of chloramphenicol, puromycin, and sparsomycin in our laboratory have provided us with several leads to the development of relatively inexpensive classes of protein synthesis inhibitors with selective toxicities. In addition, our biological studies have supported our original suggestion that synthetic compounds could be prepared and modified to fit the peptidyltransferase site of the ribosome. All of our compounds will be routinely screened for antiviral properties.